1. Field of the Invention
The present invention relates to the use of human B cell differentiation factor (abbreviated "h BCDF") for preparing compositions for treating thrombocytopenia (platelet deficiency).
More particularly, the present invention relates to the preparation of compositions for treating thrombocytopenia comprising human BCDF as the effective ingredient.
2. Description of the Background
Factors for differentiating mature B cells into antibody-producing cells in humans and mice are collectively called B cell differentiation factor (BCDF).
Human BCDF possesses activity which is important in the human body. Extensive research work in the recent past has led to the determination of the DNA sequence coding for BCDF and of the amino acid sequence of BCDF (Japanese Patent Application OPI Nos. 42688/88 and 56291/88). Further, human BCDF has been successfully produced using E. coli (Japanese Patent Application OPI No. 157996/88).
It has been found that human BCDF can be used as an immunotherapeutic agent which is effective in the treatment of infectious diseases and cancers (Japanese Patent Application No. 289007/87, OPI 63527/89).
The present inventors also found that human BCDF can be an effective supporting agent for bone marrow transplantation therapy (Japanese Patent Application No. 289007/87 and European patent application No. 89110835.9 (=ERA-350647)). However, there has been no report on the pharmaceutical effects of human BCDF on thrombocytopoiesis in order to cure platelet deficiency.
It has also been proposed to designate human BCDF as BSF-2 or interleukin 6 (IL-6) (Nature, 324, 73 (1986), EMBO. J., 6, 1219 (1987)). In this application, however, the term "BCDF" is used. Furthermore, human BCDF as used in this invention has no interferon activity and is thus different from IFN-.beta..sub.2 having interferon activity (Published European patent application No. 0220574).
Platelets are one type of blood cells which play an important role in the hematostatic mechanism of living bodies. Platelets adhere and coagulate on damaged tissue and at the same time, release intracellular components which induce a series of coagulation reactions.
There are several different forms of thrombocytopenia all of which cause reduction in platelet count. One form is hereditary thrombocytopenia. Another is idiopathic thrombocytopenic purpura, while still another is aplastic anemia. A clinically more important form of thrombocytopenia is secondary thrombocytopenia which is induced by general irradiation with X-rays, or by the administration of drugs which prevent hematopoiesis, or by similar treatments.
In many cases, secondary thrombocytopenia is caused by chemotherapy, radiotherapy, bone marrow transplantation, or the like applied to cancer patients which results in inadequate formation of bone marrow megakaryocytes. Secondary thrombocytopenia is a dangerous disease which impedes the recovery of the patient and sometimes causes death by bleeding.
A therapy for thrombocytopenia which is currently most frequently used involves platelet transfusion in order to keep the platelet count at a value of more than 20,000/.mu.l. However, in the case of bone marrow transplantation, for example, several months are required to increase the platelet count to the normal level so that transfusions of platelets inconsistent with HLA (human leukocyte antigen) are repeatedly required. As a result, anti-platelet antibody is formed and even after transfusion of platelets, the platelet count does not increase in many cases. In addition, there is also a danger of causing the likes of cytomegalovirus infection. Taking into account the fact that interstitial pneumonia is one of the three most frequent causes of postoperative death, it is preferred to keep the number of platelet transfusions as small as possible. Thrombocytopoiesis is the process in which megakaryocytic progenitor cells derived from multipotential stem cells are transformed into megakaryocytes via megakaryoblasts and platelets are then produced from megakaryocytes.
It is believed that this physiological thrombocytopoiesis would be controlled by humoral factors.
Therefore, if thrombocytopoiesis of the patient himself can be promoted by supplementing such humoral factors from an external source, bleeding would be prevented without transfusion of platelets. It can thus be expected that such administration of appropriate humoral factors would be effective for a radical treatment of thrombocytopenia.
Humoral factors which participate in thrombocytopoiesis, are thrombopoietin (TPO), megakaryocyte stimulating factor (MSF), thrombocytopoiesis stimulating factor (TSF), and the like. These factors would accentuate maturation and differentiation of megakaryocyte in vivo but the substances themselves are not yet elucidated ("IGAKU-NO-AYUMI" Progress in Medicine), 143, 528 (1987). On the other hand, it has been reported that megakaryocyte colony stimulating factor (Meg-CSF) and megakaryocyte colony potentiator (Meg-POT) are required for the formation of megakaryocyte colonies in vitro (Medical Immunology, 14, 463 (1987)).
In recent years, it has been revealed as to Meg-CSF that IL-3, GM-CSF, EPO, and the like have Meg-CSF activity ("JIKKEN IGAKU" Experimental Medicine, 5, 822 (1987)). However, with respect to the other factors, their presence is merely suggested by various physiological activity assay systems.
The amino acid sequences, DNA sequences and other parameters of these factors are, of course, also unclear. Therefore, it has not yet been possible to industrially produce pure products appropriate to be used as drugs. More importantly, there has been no report to the effect that the administration of these factors, in vivo, would increase the count of platelets in peripheral blood. No factor has been found which stimulates thrombocytopoiesis and which promotes platelet production in the patient himself when administered to the patient.